Polymeric materials for medical devices

ABSTRACT

The present invention includes biocompatible polymeric coatings, membranes, matrices, and films to be used with implantable medical devices. Medical devices containing such materials applied to a surface thereof contain a film-forming fluorous homo-polymer or copolymer containing the polymerized residue of a fluorous moiety, wherein the relative amounts of the polymerized residues of one or more moieties are effective to provide the coating and films with properties effective for use in coating implantable med devices.

FIELD OF THE INVENTION

The invention relates to the use of fluorous homo or co-polymers ascoatings and matrices for implantable medical devices. In particular,this invention relates to a fluorous homo or co-polymer employed as acarrier matrix for a therapeutic agent such that the agent may bedelivered locally and in a sustained fashion when the polymer having theagent therein is applied to an implantable medical device.

BACKGROUND OF THE INVENTION

Implantable medical devices are employed to restore the normal functionof the human body. For example, some devices are placed within a conduitlocated within the human body to restore the patency of the conduit.Other devices serve orthopedic functions such as replacing or repairingjoints or bones. These devices include, without limitation, stents,catheters, sutures, meshes, vascular grafts, shunts, filters forremoving emboli, artificial hips and bone anchors. Stents are generallya mesh tubular structure that is placed within a vessel. Stents arepercutaneously placed within the vessel whereby the stent has a firstcompressed shape for passage through the vasculature of the patient to atargeted area where it is necessary to restore the patency of thevessel. Once at the targeted area the stent is expanded into a secondshape, usually after the area has already been subject to a procedure,such as angioplasty, that opens the lumen of the vessel. Once the stentis expanded the lumen of the vessel is remodeled restoring adequateblood flow through the vessel.

A stent located within a vessel often stimulates reactions that resultin the formation of clots (thrombosis) or smooth muscle tissueproliferation (restenosis) that causes the lumen to constrict. In orderto avoid these complications, a variety of stent coatings andcompositions have been proposed that limit adverse reactions. Forexample, certain coatings reduce the stimulus the stent provides to theinjured lumen wall, thus reducing the tendency towards thrombosis orrestenosis. Alternately, the coating may deliver apharmaceutical/therapeutic agent or drug to the lumen that reducesrestenosis. Typically, the therapeutic agent is embedded within thematrix of a polymer coating that is applied to the stent. The agent isdelivered via diffusion through a bulk polymer, through pores that arecreated in the polymer structure, or by erosion of a biodegradablecoating. It is necessary to ensure that the proper amount of agent isdelivered to the targeted area. In order to deliver the therapeuticagent in a predictable manner it is necessary to ensure that a polymerwill permit proper elution.

Both bioabsorbable and biostable polymeric compositions have been usedas coatings for stents that will provide a stable platform for thepredictable delivery of a therapeutic agent. These are generallypolymeric coatings that either encapsulate a pharmaceutical/therapeuticagent or drug, e.g. taxol, rapamycin, etc., or bind such an agent to thesurface, e.g. heparin-coated stents. These coatings are applied to thestent in a number of ways, including, though not limited to, dip, spray,or spin coating processes. One class of biostable materials that hasbeen reported as coatings for stents is fluorous homopolymers.Polytetrafluoroethylene (PTFE) homopolymers. These homopolymers,however, are not soluble in any solvent at reasonable temperatures andtherefore are difficult to coat onto small medical devices whilemaintaining important features of the devices (e.g. slots in stents).

Another approach has been to employ coatings made from poly(vinylidenefluoride) homopolymers and containing pharmaceutical/therapeutic agentsor drugs for release have been suggested. Like most crystalline fluoroushomopolymers, however, these are difficult to apply as high qualityfilms onto surfaces without subjecting them to relatively hightemperatures, e.g. greater than about 125-200° C., that correspond tothe melting temperature of the polymer.

One approach to providing a more stable platform is disclosed in U.S.Pat. No. 6,746,773—Llanos that discloses methods and composition forbiocompatible coatings and films. These coatings are used on implantablemedical devices and medical devices comprising such coatings and filmsapplied to a surface thereof that is to be in contact with body tissueof a mammal. The biocompatible film provides an inert surface to be incontact with body tissue of a mammal upon implantation of the device inthe mammal. The coating and film comprise a film-forming fluorouscopolymer comprising the polymerized residue of a first moiety selectedfrom the group consisting of vinylidene fluoride (VDF) andhexafluoropropylene (HFP).

It would be advantageous to develop additional fluorous coatings forimplantable medical devices that offer a wider range of hydrophobicityand better mechanical properties. This will allow the coating to reducethrombosis, restenosis, or other adverse reactions, that may include,but do not require, the use of pharmaceutical or therapeutic agents ordrugs to achieve such affects. The coating will also possess physicaland mechanical properties effective for use at relatively low maximumtemperatures. It would also be advantageous to develop additionalfluorous coatings with various physical properties to meet deliveryparameters of a wide-range of pharmaceutical agents.

SUMMARY OF THE INVENTION

Fluorous based biocompatible coatings and films for use on implantablemedical devices are provided. The biocompatible film of the presentinvention is applied to an implantable medical device and provides aninert surface that will be in contact with body tissue of a mammal uponimplantation of the device. The coating and film comprises afilm-forming polymerized residue of one or more fluorous monomers invarying molar ratios. Fluorous polymers are typically hydrophobic andbiocompatible and are suitable for use within a conduit of a human bodysuch as a blood vessel.

The copolymers employed in the coating have varying physical andchemical properties depending on the monomers used and the respectiveratios between them. The final physical properties may also be affectedto a lesser degree by the end groups of the copolymers. Commonly usedmonomers include perfluoroether (PFE), fluorous acrylates, VDF, HFP,tetrafluoroethylene (TFE). Alternatively, the various fluorous polymersare mixed together to form blends that have varying physical properties.

In certain instances it is desirable to remove an implantable devicefrom the body after a certain time. The present invention provides aninert, low surface energy coating for implantable medical devices thatare later retrieved. For example, the low surface energy coating makeswetting of the device surface and protein deposition thereon difficultwhich could decrease the formation of thrombus on the implant, leadingto better performance of an implantable device such as a stent.

The coatings may comprise pharmaceutical or therapeutic agents inamounts effective for achieving a desired therapeutic result. Forexample thrombosis or restenosis may be reduced through the release ofagents that the coating controls. Films prepared from the fluorouscopolymer or polymer blend coatings of the present invention provide thephysical and mechanical properties required of conventional coatedmedical devices, even where maximum temperatures to which the device,coatings and films are exposed are limited to relatively lowtemperatures, e.g. less than about 100° C., preferably at about ambienttemperatures. This is particularly important when using the coating/filmto deliver pharmaceutical/therapeutic agent or drugs that are heatsensitive, or when applying the coating onto temperature-sensitivedevices such as, but not limited to, catheters.

Therapeutic agents possess a wide range of physical and chemicalproperties. These agents are expected to provide various functions toaddress one or more conditions such as inflammation, neointimal growthor thrombus that alone, or in combination, may occur after an implant isplaced. Polymers of varying properties are used to maximize thetherapeutic potential of each of these agents. For example, ahydrophilic agent may require a substantially hydrophobic polymer layerto slow the release of the agent from the polymer matrix of the coating.Addition of a third component to an established perfluorous copolymerP(VDF-co-HFP) may provide such required flexibility of the polymer. Forinstance, the addition of vinyl acetate or a styrene component toP(VDF-co-HFP), thereby producing P(VDF-co-HFP-co-vinyl acetate) orP(VDF-co-HFP-co-styrene), respectively, will likely strengthen thecoating matrix and likely result in a prolonged release of an agent fromthe drug/polymer matrix. The molar ratio of the combined residues of VDFand HFP to the vinyl acetate can be in a range from 0.95:0.05 to0.1:0.9.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the fraction of drug released as a function of timefrom coatings of the present invention over which no topcoat has beendisposed.

FIG. 2 illustrates the fraction of drug released as a function of timefrom coatings of the present invention including a topcoat disposedthereon.

FIG. 3 illustrates the fraction of drug released as a function of timefrom coatings of the present invention over which no topcoat has beendisposed.

FIG. 4 illustrates in vivo stent release kinetics of rapamycin frompoly(VDF/HFP).

FIG. 5 shows the chemical structure of Krytox oligomer terminated withan iodine atom.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polymeric coatings comprising a fluorouscopolymer that may be applied to an implantable medical device such as astents or orthopedic implant. The device will be coated with a film ofthe fluorous polymeric material in an amount effective to reducethrombosis and/or restenosis when the device is implanted within aconduit of a human.

As used herein, fluorous copolymers means those copolymers comprisingthe polymerized residue selected from the group consisting of vinylidenefluoride (VDF), perfluoropolyethers (PFPE), and tetrafluoroethylene(TFE), perfluorous acrylate (PFL), hexafluoropropylene (HFP) amongothers. The molar ratios of these monomers may be adjusted such that thefinal copolymers may be most optimal as a drug delivery matrixassociated with a medical device with a desirable toughness orelastomeric properties effective for use in coating implantable medicaldevices.

The present invention comprises fluorous copolymers and polymer blendsthat provide improved biocompatible coatings for medical devices. Thesecoatings provide inert surfaces that reduce thrombosis, restenosis, andother undesirable reactions. While most reported coatings made fromfluorous homopolymers such as PTFE are insoluble in regular organicsolvent such as tetrahydrofuran (THF), and/or require high heat, e.g.greater than about 125° C., to obtain films with adequate physical andmechanical properties for use on implantable devices, e.g. stents, orare not particularly tough or elastomeric, films prepared from fluorouscopolymer and polymer blend coatings of the present invention provideadequate adhesion, toughness or elasticity, and resistance to crackingwhen formed on medical devices claimed herein. In certain embodiments,this is the case even where the coated devices are subjected torelatively low maximum temperatures, e.g. less than about 100° C.,preferably less than about 60° C., and more preferably about 40° C. orless.

The fluorous copolymers and polymer blends used as drug deliverymatrices or coatings according to the present invention are polymersthat have molecular weight high enough so as not to be waxy or tacky.The polymers and films formed therefrom adhere to the stent and are notreadily deformable after deposition on the stent preventing them frombeing displaced by hemodynamic stresses. The polymer molecular weightprovides sufficient toughness so that the polymer coating will not berubbed off during handling or deployment of the device. In certainembodiments the coating will not crack during expansion of a deviceduring deployment in a conduit.

Coatings of the present invention comprise fluorous copolymers, asdefined hereinabove. The first, second, and third moiety copolymerizedwith the first moiety to prepare the fluorous copolymer may be selectedfrom those biocompatible monomers that would provide biocompatiblepolymers acceptable for implantation in a mammal, while maintainingsufficient elastomeric film properties for use on medical devicesclaimed herein. Such monomers include, without limitation,hexafluoropropylene (HFP), tetrafluoroethylene (TFE), vinylidenefluoride (VDF), perfluoropolyethers (PFPE), and tetrafluoroethylene(TFE), perfluorous acrylate (PFL), hexafluoropropylene (HFP) andhexafluoroisobutylene. Each of these monomers will bring a unique set ofdesirable properties to the final copolymer. For instance,perfluoroether is inert, transparent, and chemical and thermally stable.Depending on the needs as a coating for medical devices, AB or ABA typecopolymers may be created from the above monomers to tailor the physicaland chemical properties of the final copolymers or blends. The ratios ofthe monomers should also be tailored so that the fluorous copolymers andblends are soluble, in varying degrees, in solvents such asdimethylacetamide (DMAc), tetrahydrofuran, dimethyl formamide, dimethylsulfoxide and n-methylpyrrolidone for easy processing. Some are solublein methylethylketone (MEK), acetone, methanol and other solventscommonly used in applying coatings to conventional implantable medicaldevices.

Conventional fluorous homopolymers are crystalline and difficult toapply as high quality films onto metal surfaces without exposing thecoatings to relatively high temperatures that correspond to the meltingtemperature (Tm) of the polymer. The elevated temperature serves toprovide films prepared from such PVDF homopolymer coatings that exhibitsufficient adhesion of the film to the device, while preferablymaintaining sufficient flexibility to resist film cracking uponexpansion/contraction of the coated medical device. Certain films andcoatings according to the present invention provide these same physicaland mechanical properties, or essentially the same properties, even whenthe maximum temperatures to which the coatings and films are exposed isless than about 100° C., and preferably less than about 65° C. This isuseful when the coating includes pharmaceutical or therapeutic agentsthat are heat sensitive, e.g. subject to chemical or physicaldegradation or other heat-induced negative affects, or when coating heatsensitive substrates of medical devices, e.g. subject to heat-inducedcompositional or structural degradation.

Depending on the particular device upon which the coatings and films ofthe present invention are to be applied and the particular use/resultrequired of the device, fluorous copolymers used to prepare such devicesmay be crystalline, semi-crystalline or amorphous. Semi-crystalline andamorphous fluorous copolymers are advantageous where exposure toelevated temperatures is an issue, e.g. where heat-sensitivepharmaceutical or therapeutic agents are incorporated into the coatingsand films, or where device design, structure and/or use precludeexposure to such elevated temperatures. Semi-crystalline fluorouscopolymer elastomers comprising relatively high levels, e.g. from about30 to about 45 weight percent of the second moiety, e.g. HFP,copolymerized with the first moiety, e.g. VDF, have the advantage ofreduced coefficient of friction and self-blocking relative to amorphousfluorous copolymer elastomers. Such characteristics can be of value whenprocessing, packaging and delivering medical devices coated with suchfluorous copolymers. In addition, such fluorous copolymer elastomerscomprising such relatively high content of the second moiety serves tocontrol the solubility of certain agents, e.g. Sirolimus, in the polymerand therefore controls permeability of the agent through the matrix.

Fluorous copolymers utilized in the present inventions may be preparedby various known polymerization methods. For example, high pressure,free-radical, semi-continuous emulsion polymerization techniques such asthose disclosed in Fluoroelastomers-dependence of relaxation phenomenaon composition, POLYMER 30, 2180, 1989, by Ajroldi, et al, may beemployed to prepare amorphous fluorous copolymers, some of which may beelastomers. In addition, free-radical batch emulsion polymerizationtechniques disclosed herein may be used to obtain polymers that aresemi-crystalline, even where relatively high levels of the secondmoiety, e.g. greater than about 19-20 mole percent (equivalent to about36-37 weight percent), are included.

Implantable medical devices such as stents may be coated with a film ofa fluorous copolymer or polymer blend according to the presentinvention. Conventional stents are used in transluminal procedures suchas angioplasty to restore adequate blood flow to the heart and otherorgans. They generally are cylindrical and perforated with passages thatare slots, ovoid, circular or the like shape. Stents also may becomposed of helically wound or serpentine wire structures in which thespaces between the wires form passages. Stents may be flat perforatedstructures that are subsequently rolled to form tubular or cylindricalstructures that are woven, wrapped, drilled, etched or cut to formpassages. Examples of stents that may be advantageously coated byfluorous copolymers or blends of the present invention include, but arenot limited to, stents described in U.S. Pat. Nos. 4,733,665; 4,800,882;4,886,062, 5,514,154, and 6,190,403, the contents each of which isincorporated herein in its entirety as if set forth herein. These stentscan be made of biocompatible materials, including biostable andbioabsorbable materials. Suitable biocompatible metals include, but arenot limited to, stainless steel, tantalum, titanium alloys (includingnitinol), and cobalt alloys (including cobalt-chromium-nickel alloys).Suitable nonmetallic biocompatible materials include, but are notlimited to, polyamides, polyolefins (i.e. polypropylene, polyethyleneetc.), nonabsorbable polyesters (i.e. polyethylene terephthalate), andbioabsorbable aliphatic polyesters (i.e. homopolymers and copolymers oflactic acid, glycolic acid, lactide, glycolide, para-dioxanone,trimethylene carbonate, ε-caprolactone, and blends thereof).

The biocompatible polymer coatings generally are applied to the stent inorder to reduce local turbulence in blood flow through the stent, aswell as adverse tissue reactions. The coatings and films formedtherefrom also may be used to administer a pharmaceutically activematerial to the site of the stent placement. Generally, the amount ofpolymer coating to be applied to the stent will vary depending on, amongother possible parameters, the particular fluorous copolymers and blendsused to prepare the coating, the stent design, and the desired effect ofthe coating. Generally, the coated stent will comprise from about 0.1 toabout 15 weight percent of the coating, preferably from about 0.4 toabout 10 weight percent. The fluorous copolymer coatings may be appliedin one or more coating steps, depending on the amount of fluorouscopolymer to be applied. Different fluorous copolymers may be used fordifferent layers in the stent coating. A diluted first coating solutioncan be used that comprises a fluorous copolymer as a primer to promoteadhesion of a subsequent fluorous copolymer coating layer that maycontain pharmaceutically active materials. The individual coatings maybe prepared from different fluorous copolymers or polymer blends.

Additional coatings can be applied to delay release of thepharmaceutical agent. In addition, the polymer matrix of an additionalcoating can be used for the delivery of a different agent. Thus, thelayering of coatings can also be employed to stage the release of theagent or to control release of different agents placed in differentlayers. As will be readily appreciated by those skilled in the artnumerous layering approaches can be used to provide the desired drugdelivery. Similarly, fluorous polymer blends may also be used toconstruct alternate layers of drug containing matrices.

Blends of fluorous copolymers may be used to control the release rate ofdifferent agents or to provide desirable balance of coating properties,i.e. elasticity, toughness, etc., and drug delivery characteristics,e.g. release profile. Fluorous copolymers with different solubility insolvents can be used to build up different polymer layers that may beused to deliver different drugs or to control the release profile of adrug. For example, fluorous copolymers comprising 85.5/14.5 (wt/wt) ofpoly(VDF/HFP) and 60.6/39.4 (wt/wt) of poly(VDF/HFP) are both soluble inDMAc. However, only the 60.6/39.4 poly(VDF/HFP) fluorous copolymer issoluble in methanol. A first layer of the 85.5/14.5 poly(VDF/HFP)fluorous copolymer comprising a drug could be over-coated with a topcoatof the 60.6/39.4 poly(VDF/HFP) fluorous copolymer made with the methanolsolvent.

The coatings can be used to deliver therapeutic and pharmaceuticalagents such as, but not limited to: antiproliferative/antimitotic agentsincluding natural products such as vinca alkaloids (i.e. vinblastine,vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e.etoposide, teniposide), antibiotics (dactinomycin (actinomycin D)daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone,bleomycins, plicamycin (mithramycin) and mitomycin, enzymes(L-asparaginase which systemically metabolizes L-asparagine and deprivescells which don't have the capacity to synthesize their own asparagine);antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);Anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);antiinflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetominophen; Indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); Angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF); nitric oxide donors; cell cycle inhibitors; mTORinhibitors; growth factor signal transduction knase inhibitors;anti-sense oligonucleotide; prodrug molecules; and combinations thereof.

According to the present invention, coatings may be formulated by mixingone or more therapeutic agents with fluorous copolymers in a coatingmixture. The therapeutic agent may be present as a liquid, a finelydivided solid, or any other appropriate physical form. Optionally, thecoating mixture may include one or more additives, e.g., nontoxicauxiliary substances such as diluents, carriers, excipients, stabilizersor the like. Other suitable additives may be formulated with the polymerand pharmaceutically active agent or compound. For example, ahydrophilic polymer may be added to a biocompatible hydrophobic coatingto modify the release profile, or a hydrophobic polymer may be added toa hydrophilic coating to modify the release profile. One example wouldbe adding a hydrophilic polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol,carboxylmethyl cellulose, and hydroxymethyl cellulose to a fluorouscopolymer coating to modify the release profile.

The fluorous copolymer and pharmaceutical agent may have a commonsolvent. This provides a wet coating that is a true solution. Inaddition, coatings that contain the agent as a solid dispersion in asolution of the polymer in solvent may be employed. Under the dispersionconditions, the particle size of the dispersed powder of the agent, boththe primary powder size and its aggregates and agglomerates, is smallenough not to cause an irregular coating surface or to clog the slots ofthe stent that need to remain essentially free of coating. In caseswhere a dispersion is applied to the stent and the smoothness of thecoating film surface requires improvement, or to be ensured that allparticles of the drug are fully encapsulated in the polymer, or in caseswhere the release rate of the drug is to be slowed, a clear (fluorouscopolymer only) topcoat of the same fluorous copolymer used to providesustained release of the drug or another fluorous copolymer that furtherrestricts the diffusion of the drug out of the coating can be applied.

The topcoat can be applied to a device, for example a stent, by dipcoating with a mandrel to clear the matrix of the stent. This techniqueis commonly referred to as the dip and wipe method which is described ingreater detail in U.S. Pat. No. 6,153,252, the contents of which areincorporated herein in their entirety. Other methods for applying thetopcoat include spin coating and spray coating. A clear coating solutioncan be used that acts as a zero concentration sink and re-dissolvespreviously deposited drug. The time spent in the dip bath may need to belimited so that the drug is not extracted out into the drug-free bath.Drying is usually rapid so that the previously deposited drug does notcompletely diffuse into the topcoat.

The quantity and type of fluorous copolymers employed in the coatingcontaining the pharmaceutical agent will vary depending on the releaseprofile desired and the amount of drug employed. The product may containblends of the same or different fluorous copolymers having differentmolecular weights to provide the desired release profile or consistencyto a given formulation.

Fluorous copolymer or blend coatings may release dispersed drug bydiffusion. This can result in prolonged delivery (over, 1 to 2,000hours, preferably 2 to 800 hours) of effective amounts (say, 0.001μg/cm²-min to 100 μg/cm²-min) of the drug. The dosage can be tailored tothe subject being treated, the severity of the affliction, the judgmentof the prescribing physician, and the like. Individual formulations ofdrugs and fluorous copolymers may be tested in appropriate in vitro andin vivo models to achieve the desired drug release profiles. Forexample, a drug could be formulated with a fluorous copolymer, or blendof fluorous copolymers, coated onto a stent and placed in an agitated orcirculating fluid system, e.g. 25% ethanol in water. Samples of thecirculating fluid could be taken to determine the release profile (suchas by HPLC, UV analysis or use of radiotagged molecules). The release ofa pharmaceutical compound from a stent coating into the interior wall ofa lumen could be modeled in an appropriate animal system. The drugrelease profile could then be monitored by appropriate means such as, bytaking samples at specific times and assaying the samples for drugconcentration (using HPLC to detect drug concentration). Thrombusformation can be modeled in animal models using the ¹¹¹In-plateletimaging methods described by Hanson and Harker, Proc. Natl. Acad. Sci.USA 85:3184-3188 (1988). Following this or similar procedures, thoseskilled in the art will be able to formulate a variety of stent coatingformulations.

While not a requirement of the present invention, the coatings and filmsmay be crosslinked once applied to the medical devices. Crosslinking maybe affected by any of the known crosslinking mechanisms, such aschemical, heat or light. In addition, crosslinking initiators andpromoters may be used where applicable and appropriate. In thoseembodiments utilizing crosslinked films comprising pharmaceuticalagents, curing may affect the rate at which the drug diffuses from thecoating. Crosslinked fluorous copolymers films and coatings of thepresent invention also may be used without drug to modify the surface ofimplantable medical devices.

EXAMPLES Example 1 Use of PVDF Homopolymer and Fluorous Copolymers ofPoly(VDF/HFP)

Use of a poly(VDF) homopolymer (Solef 1008 from Solvay AdvancedPolymers, Houston, Tex., Tm about 175° C.) and fluorous copolymers ofpoly(VDF/HFP), 92/8 and 91/9 weight percent VDF/HFP, respectively, asdetermined by F¹⁹ NMR (eg: Solef 11010 and 11008, Solvay AdvancedPolymers, Houston, Tex., Tm about 159° C. and 160° C., respectively)were examined as potential coatings for stents. These polymers aresoluble in solvents such as, but not limited to, DMAc,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N-methylpyrrolidone IMP), tetrahydrofuran (THF) and acetone. Polymercoatings were prepared by dissolving the polymers in acetone, at 5weight percent as a primer, or by dissolving the polymer in 50/50DMAc/acetone, at 30 weight percent as a topcoat. Coatings that wereapplied to the stents by dipping and dried at 60° C. in air for severalhours, followed by 60° C. for 3 hours in a <100 mm Hg vacuum, resultedin white foamy films. As applied, these films adhered poorly to thestent and flaked off, indicating they were too brittle. When stentscoated in this manner were heated above 175° C., i.e. above the meltingtemperature of the polymer, a clear, adherent film was formed. Suchcoatings require high temperatures, e.g. above the melting temperatureof the polymer, to achieve high quality films.

Example 2 A Fluorous Copolymer (Solef 21508) Comprising 85.5 WeightPercent VDF Copolymerized with 14.5 Weight Percent HFP, as Determined byF¹⁹ NMR

This copolymer is less crystalline than the fluorous homopolymer andcopolymers described in Example 1. It also has a lower melting pointreported to be about 133° C. Once again, a coating comprising about 20weight percent of the fluorous copolymer was applied from a polymersolution in 50/50 DMAc/MEK. After drying (in air) at 60° C. for severalhours, followed by 60° C. for 3 hours in a <100 mtorr Hg vacuum, clearadherent films were obtained. This eliminated the need for a hightemperature heat treatment to achieve high quality films. Coatings weresmoother and more adherent than those of Example 1. Some coated stentsthat underwent expansion show some degree of adhesion loss and “tenting”as the film pulls away from the metal. Where necessary, modification ofcoatings containing such copolymers may be made, e.g. by addition ofplasticizers or the like to the coating compositions. Films preparedfrom such coatings may be used to coat stents or other medical devices,particularly where those devices are not susceptible to expansion to thedegree of the stents.

The coating process in Example 1 above was repeated, this time with acoating comprising the 85.5/14.6 (wt/wt) (VDF/HFP) and about thirty (30)weight percent of rapamycin (Wyeth-Ayerst Laboratories, Philadelphia,Pa.), based on total weight of coating solids. Clear films that wouldoccasionally crack or peel upon expansion of the coated stents resulted.Inclusion of plasticizers and the like in the coating composition willresult in coatings and films for use on stents and other medical devicesthat are not susceptible to such cracking and peeling.

Example 3 Fluorous Copolymers Having Higher HFP Content

This series of polymers were not semi-crystalline, but rather aremarketed as elastomers. One such copolymer is Fluorel FC-2261Q (fromDyneon, a 3M-Hoechst Enterprise, Oakdale, Minn.), a 60.6/39.4 (wt/wt)copolymer of VDF/HFP. Although this copolymer has a glass transitiontemperature (Tg) well below room temperature (Tg about −20° C.), it isnot tacky at room temperature or even at 60° C. This polymer has nodetectable crystallinity when measured by Differential ScanningCalorimetry (DSC) or by wide angle X-ray diffraction. Films formed onstents as described above were non-tacky, clear, and expanded withoutincident when the stents were expanded.

The coating process in Example 1 above was repeated, this time withcoatings comprising the 60.6/39.4 (wt/wt) poly(VDF/HFP) and about nine(9), thirty (30) and fifty (50) weight percent of rapamycin, based ontotal weight of coating solids, respectively. Coatings comprising about9 and 30 weight percent rapamycin provided white, adherent, tough filmsthat expanded without incident on the stent. Inclusion of 50% drug, inthe same manner, resulted in some loss of adhesion upon expansion.

Changes in the co-monomer composition of the fluorous copolymer also canaffect the nature of the solid-state coating, once dried. For example,the semi-crystalline copolymer, Solef 21508, containing 85.5% VDFpolymerized with 14.5% by weight HFP forms homogeneous solutions withabout 30% rapamycin (drug weight divided by total solids weight, e.g.drug plus copolymer) in DMAc and 50/50 DMAc/MEK. When the film is dried(60° C./16 hours followed by 60° C./3 hours in vacuum of 100 mm Hg) aclear coating, indicating a solid solution of the drug in the polymer,is obtained. Conversely, when an amorphous copolymer, Fluorel FC-2261Q,of poly(VDF/HFP) at 60.6/39.5 (wt/wt) forms a similar 30% solution ofrapamycin in DMAc/MEK and is similarly dried, a white film, indicatingphase separation of the drug and the polymer, is obtained. This seconddrug containing film is much slower to release the drug into an in vitrotest solution of 25% ethanol in water than is the former clear film ofcrystalline Solef 21508. X-ray analysis of both films indicates that thedrug is present in a non-crystalline form. Poor or very low solubilityof the drug in the high HFP-containing copolymer results in slowpermeation of the drug through the thin coating film. Permeability isthe product of diffusion rate of the diffusing species (in this case thedrug) through the film (the copolymer) and the solubility of the drug inthe film.

Example 4 In Vitro Release Results of Rapamycin from Coating

FIG. 1 is a plot of data for the 85.5/14.5 VDF/HFP fluorous copolymer,indicating fraction of drug released as a function of time, with notopcoat. FIG. 2 is a plot of data for the same fluorous copolymer overwhich a topcoat has been disposed indicating that most effect on releaserate is with a clear topcoat. As shown therein, TC150 refers to a devicecomprising 150 micrograms of topcoat, TC235 refers to 235 micrograms oftopcoat, etc. The stents before top coating had an average of 750micrograms of coating containing 30% rapamycin (based ondrug/[drug+polymer]). FIG. 3 is a plot for the 60.6/39. 4 VDF/HFPfluorous copolymer, indicating fraction of drug released as a functionof time, showing significant control of release rate from the coatingwithout the use of a topcoat. Loading of the drug in the film controlsrelease.

Example 5 In Vivo Testing of Coated Stents in Porcine Coronary Arteries

CrossFlex® stents (available from Cordis Corporation) were coated withthe “as received” Fluorel FC-2261Q PVDF copolymer and with the purifiedfluorous copolymer of example 6, using the dip and wipe approach. Thecoated stents were sterilized using ethylene oxide and a standard cycle.The coated stents and bare metal stents (controls) were implanted inporcine coronary arteries, where they remained for 28 days. Angiographywas performed immediately after implantation and at 28 days. Angiographyindicated that the control uncoated stent exhibited about 21 percentrestenosis. The fluorous copolymer “as received” exhibited about 26%restenosis (equivalent to the control) and the washed copolymerexhibited about 12.5% restenosis. Histology results reported neointimalarea at 28 days to be 2.89±0.2, 3.57±0.4 and 2.75±0.3, respectively, forthe bare metal control, the unpurified copolymer and the purifiedcopolymer. The in vivo release of rapamycin from the polymer-coatingmatrix is shown in FIG. 4.

Example 6 Preparation of Semi-Crystalline, Poly(VDF/HFP) CopolymerElastomers

The VDF and HFP monomers were premixed under pressure in a pressurevessel. HPLC-grade water, surfactant and initiator were mixed outside ofa 2 liter Zipperclave® reactor (Autoclave Engineers, Erie, Pa.) and thencharged to the reactor, which then was sealed. The premixed monomersthen were transferred under nitrogen pressure to the reactor. Whilestirring, the reactor was raised to the desired temperature and held fora predetermined period of time. The reactor then was cooled and residualmonomer vented. The resultant polymer latex was removed from the reactorand coagulated or crashed by adding dilute hydrochloric acid, followedby aqueous sodium chloride. The resulting polymer was washed extensivelywith water and dried.

The fluorous copolymers then were compared with respect to kineticcoefficient of friction of a film prepared therefrom to the kineticcoefficient of friction of a film prepared from a commercial amorphousfluorous copolymer comprising 59.5 weight percent VDF copolymerized with40.5 weight percent HFP utilizing the following procedure.

A 57.2 mm wide by 140.0 mm long polymer film was cast on a 101.6 mm wideby 203.2 mm long aluminum panel (Q-panel, anodized finish, A-48). Asilicone rubber gasket was placed on the aluminum panel and clampedusing binder clips. The mold was leveled in a fume hood using a bubblelevel. Approximate 5.0 g of 10.0% polymer solution in methyl ethylketone was poured into the mold slowly. The film was dried at roomtemperature for 3 days followed by 3 hours at 23° C. and 50% R.H. priorto testing.

The kinetic coefficient of friction of the polymer film was measured inaccordance with the method described in ASTM D 1894-00, “Static andKinetic Coefficients of Friction of Plastic Film and Sheeting”, MethodC. A 46.5 g Teflon block, 25.4 mm wide by 41.3 mm long by 19.1 mm thick,with an eye screw fastened in one end was used as a sled. The surface ofthe sled that contacted to the film was polished using 500-gritsandpaper. The Teflon sled was attached to a flexible beaded chain andpulled using an Instron tensile tester at a rate of 150 mm/min., at 23°C. and 50% R.H. Five measurements was made on each film sample. Thethickness of the film was measured using a digital thickness gauge. Thekinetic coefficient test results are given in Table 1. The maximumkinetic coefficient of friction of five measurements of each film wereaveraged and reported.

The Differential Scanning Calorimetry (DSC) data were obtained on thefollowing polymers using vacuum dried films in a TA Instruments Model2920 Modulated DSC in standard (non-modulated) DSC mode. The sampleswere quenched to −80° C. and heated at 10° C./min to 275° C. innitrogen. The data are reported as ΔH (J/g) for endothermic, meltingevents above glass transition temperature (Tg).

Example 7 Synthesis of Grafted PVDF HFP PFPE Terpolymers

Monomers of VDF and HFP and allyl amide type perfluoropolyether were putinto a pressurized reaction vessel as predetermined molar ratios. Thepolymerization is initiated by tert-butyl peroxide at 140° C. inperfluorohexane/acetonitrile mixture. The reaction is monitored by thedecrease of pressure inside the vessel. The crude grafted polymer isprecipitated in hexane yielding the final terpolymer. The reactionscheme is illustrated in below.

1. An implantable medical device having at least one pharmaceuticalagent contained within a biocompatible coating applied to the devicewherein said coating comprises a single, hydrophobic fluorous copolymerof polymerized residues of vinylidene fluoride, hexafluoropropylene, andvinyl acetate, the copolymer having the formula P(VDF-co-HFP-co-vinylacetate), the coating modifying the surface of the medical device. 2.The implantable medical device of claim 1 wherein said device comprisesa stent.
 3. The implantable medical device of claim 1 wherein the atleast one pharmaceutical agent comprises an anti-inflammatory agent. 4.The implantable medical device of claim 1 wherein the at least onepharmaceutical agent comprises an anti-restenotic agent.
 5. Theimplantable medical device of claim 1 wherein the coating includes atherapeutic agent and an anti-thrombotic agent.
 6. The implantablemedical device of claim 1 wherein the molar ratio of the combinedresidues of vinylidene fluoride and hexafluoropropylene HFP to vinylacetate is in a range from 0.95:0.05 to 0.1:0.9.
 7. An implantablemedical device having at least one pharmaceutical agent contained withina biocompatible coating applied to the device wherein said coatingcomprises a random hydrophobic fluorous copolymer of fluoridatedmonomers and styrene, the coating modifying the surface of the medicaldevice.